Selective androgen receptor modulators (SARMs) and uses thereof

Abstract

Provided herein are compounds, such as compounds of Formula I, that bind to androgen receptors and/or modulate activity of androgen receptors. Also provided are methods for making and using such compounds. Also provided are compositions including such compounds and methods for making and using such compositions.

The invention claimed is: 
     
       1. A method of treating a disease, disorder or condition selected from the group consisting of osteopenia, bone damage and bone fracture in a subject having said disease, disorder or condition comprising:
 administering to the subject a therapeutically effective amount of a compound of formula I; 
 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is CF 3 , F or Cl; 
         R 2  is H or methyl; and 
         R 3  is H or methyl, 
         or a pharmaceutically acceptable salt or ester thereof, 
         thereby treating the disease, disorder or condition. 
       
     
     
       2. The method of  claim 1 , wherein R 1  is CF 3 , R 2  is H and R 3  is H. 
     
     
       3. The method of  claim 1 , wherein R 1  is CF 3 , R 2  is H and R 3  is methyl. 
     
     
       4. The method of  claim 1 , wherein R 1  is CF 3 , R 2  is methyl and R 3  is hydrogen. 
     
     
       5. The method of  claim 1 , wherein R 1  is F or Cl, R 2  is H and R 3  is H. 
     
     
       6. The method of  claim 1 , wherein R 1  is F or Cl, R 2  is H and R 3  is methyl. 
     
     
       7. The method of  claim 1 , wherein R 1  is F or Cl, R 2  is methyl and R 3  is hydrogen. 
     
     
       8. The method of  claim 1 , wherein the compound of formula I is selected from among:
 R,R-4-(2-(1-Hydroxyl-2,2,2-trifluoroethyl)pyrrolidinyl)-2-trifluoromethyl-benzonitrile; 
 4-(2(R)-(1(S)-hydroxyl-2,2,2-trifluoroethyl)pyrrolidinyl)-2-trifluoromethyl-benzonitrile; 
 R,R,R-4-(2-(1-Hydroxyl-2,2,2-trifluoroethyl)-5-methylpyrrolidinyl)-2-trifluoromethyl-benzonitrile; 
 4-(2(R)-(1(S)-hydroxyl-2,2,2-trifluoroethyl)-5(R)-methylpyrrolidinyl)-2-trifluoromethyl-benzonitrile; 
 R,R-4-(2-(1-Hydroxyl-2,2,2-trifluoroethyl)pyrrolidinyl)-2-chlorobenzonitrile; 
 4-(2(R)-(1(S)-hydroxyl-2,2,2-trifluoroethyl)pyrrolidinyl)-2-chlorobenzonitrile; 
 R,R,R-4-(2-(1-hydroxyl-2,2,2-trifluoroethyl)-5-methylpyrrolidinyl)-2-chlorobenzonitrile; 
 4-(2(R)-(1(S)-hydroxyl-2,2,2-trifluoroethyl)-5(R)-methylpyrrolidinyl)-2-chlorobenzonitrile; 
 R,R-4-(2-(1-hydroxyl-2,2,2-trifluoroethyl)pyrrolidinyl)-2-chloro-3-methylbenzonitrile; 
 4-(2(R)-(1(S)-hydroxyl-2,2,2-trifluoroethyl)-pyrrolidinyl)-2-chloro-3-methylbenzonitrile; 
 3-methyl-4-((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)-benzonitrile; 
 3-methyl-4-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)-benzonitrile; 
 3-methyl-4-((2R,5R)-2-methyl-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile; 
 2-fluoro-4-((2R,5R)-2-methyl-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-pyrrolidin-1-yl)-benzonitrile; 
 2-fluoro-3-methyl-4-((2R,5R)-2-methyl-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-pyrrolidin-1-yl)benzonitrile; 
 2-fluoro-3-methyl-4-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-benzonitrile; 
 2-fluoro-4-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)benzonitrile; 
 2-chloro-4-((2R,5R)-2-methyl-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-pyrrolidin-1-yl)-benzonitrile; 
 2-chloro-3-methyl-4-((2R,5R)-2-methyl-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-pyrrolidin-1-yl)benzonitrile; 
 2-chloro-3-methyl-4-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-benzonitrile; and 
 2-chloro-4-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-benzonitrile; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       9. The method of  claim 1 , wherein the compound of formula I is 4-(2(R)-(1(S)-hydroxyl-2,2,2-trifluoroethyl)pyrrolidinyl)-2-trifluoromethyl-benzonitrile, or a pharmaceutically acceptable salt thereof. 
     
     
       10. The method of  claim 1 , wherein the disease, disorder or condition is a bone fracture. 
     
     
       11. The method of  claim 10 , wherein the bone fracture is a hip fracture. 
     
     
       12. The method of  claim 1 , wherein the bone fracture is treated by accelerating bone fracture repair. 
     
     
       13. The method of  claim 12 , wherein the bone fracture is a hip fracture. 
     
     
       14. The method of  claim 12 , wherein the compound of formula I is 4-(2(R)-(1(S)-hydroxyl-2,2,2-trifluoroethyl)pyrrolidinyl)-2-trifluoromethyl-benzonitrile, or a pharmaceutically acceptable salt thereof. 
     
     
       15. The method of  claim 14 , wherein the bone fracture is a hip fracture.